InChI | InChI=1S/C57H87N7O15/c1-15-33(8)46-44(66)29-45(67)79-49(32(6)7)48(68)34(9)50(69)58-39(26-30(2)3)54(73)64-25-17-19-41(64)56(75)62(13)43(28-37-20-22-38(77-14)23-21-37)57(76)78-36(11)47(52(71)59-46)60-51(70)42(27-31(4)5)61(12)55(74)40-18-16-24-63(40)53(72)35(10)65/h20-23,30-34,36,39-44,46-47,49,66H,15-19,24-29H2,1-14H3,(H,58,69)(H,59,71)(H,60,70)/t33-,34-,36+,39-,40-,41-,42+,43-,44-,46+,47-,49-/m0/s1 |
Reference | [1]. Drug Des Devel Ther. 2017 Jan 19;11:253-264. doi: 10.2147/DDDT.S94165. eCollection 2017.<br />
Plitidepsin: design, development, and potential place in therapy.<br />
Alonso-Álvarez S(1), Pardal E(2), Sánchez-Nieto D(3), Navarro M(4), Caballero MD(1), Mateos MV(1), Martín A(1).<br />
Author information: (1)Hematology Department, IBSAL-CIC-USAL, Hospital Universitario de Salamanca, Salamanca, Spain. (2)Hematology Department, Hospital Virgen del Puerto, Plasencia, Spain. (3)Pharmacy Department, Hospital Universitario de Salamanca, Salamanca, Spain. (4)Oncology Department, Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain.<br />
Plitidepsin is a cyclic depsipeptide that was first isolated from a Mediterranean marine tunicate (Aplidium albicans) and, at present, is manufactured by total synthesis and commercialized as Aplidin®. Its antitumor activity, observed in preclinical in vitro and in vivo studies has prompted numerous clinical trials to be conducted over the last 17 years, alone or in combination with other anticancer agents. Single-agent plitidepsin has shown limited antitumor activity and a tolerable safety profile in several malignancies, such as noncutaneous peripheral T-cell lymphoma, melanoma, and multiple myeloma. In patients with relapsed or refractory multiple myeloma, plitidepsin activity seems to be enhanced after addition of dexamethasone while remaining well tolerated, and a Phase III trial comparing plitidepsin plus dexamethasone vs dexamethasone alone is underway. Additional studies are required to better define the role of plitidepsin in combination with other active agents in these indications. Results of plitidepsin activity in other hematological malignancies or solid tumors have been disappointing so far. Further studies analyzing its mechanisms of action and potential biomarkers will help select patients who may benefit most from this drug. In this review, we critically analyze the published studies on plitidepsin in hematological malignancies and solid tumors and discuss its current role and future perspectives in treating these malignancies. We also review its design, pharmaceutical data, and mechanism of action.<br />
DOI: 10.2147/DDDT.S94165 PMCID: PMC5261604 PMID: 28176904 [Indexed for MEDLINE]<br />
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[2]. Aust Prescr. 2019 Oct;42(5):172-173. doi: 10.18773/austprescr.2019.059. Epub 2019 Sep 13.<br />
Plitidepsin for multiple myeloma.<br />
DOI: 10.18773/austprescr.2019.059 PMCID: PMC6787298 PMID: 31631934<br />
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[3]. Future Oncol. 2019 Jan;15(2):109-120. doi: 10.2217/fon-2018-0492. Epub 2018 Aug 16.<br />
Plitidepsin: a potential new treatment for relapsed/refractory multiple myeloma.<br />
Leisch M(1), Egle A(1), Greil R(1).<br />
Author information: (1)Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology & Rheumatology, Oncologic Center, Salzburg Cancer Research Institute – Laboratory of Immunological & Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Salzburg, Austria, Cancer Cluster Salzburg, Austria.<br />
Plitidepsin is a marine-derived anticancer compound isolated from the Mediterranean tunicate Applidium albicans. It exerts pleiotropic effects on cancer cells, most likely by binding to the eukaryotic translation eEF1A2. This ultimately leads to cell-cycle arrest, growth inhibition and induction of apoptosis via multiple pathway alterations. Recently, a Phase III randomized trial in patients with relapsed/refractory multiple myeloma reported outcomes for plitidepsin plus dexamethasone compared with dexamethasone. Median progression-free survival was 3.8 months in the plitidepsin arm and 1.9 months in the dexamethasone arm (HR: 0.611; p = 0.0048). Here, we review preclinical data regarding plitidepsins mechanism of action, give an overview of clinical trial results across different tumor types as well as the latest results in multiple myeloma.<br />
DOI: 10.2217/fon-2018-0492 PMID: 30111169<br />
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[4]. Drugs Today (Barc). 2020 May;56(5):337-347. doi: 10.1358/dot.2020.56.5.3135886.<br />
Plitidepsin to treat multiple myeloma.<br />
Gomes NGM(1), Valentão P(1), Andrade PB(1), Pereira RB(2).<br />
Author information: (1)REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal. (2)REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal. [email protected].<br />
While remaining relatively rare, multiple myeloma (MM) accounts for approximately 10% of all hematological malignancies, being an insidious disease with an overall 5-year survival rate of 52%. In addition to other associated complications, myeloma bone disease further aggravates MM patients, the majority of whom suffer from lytic lesions, leading to pain, fractures, mobility issues and neurological deficits. Patients not responding or becoming resistant to prior therapies have now a novel therapeutic tool with an unprecedent mode of action, differing from those currently in use. The anticancer effects of the marine-derived antitumor agent plitidepsin primarily rely on the interaction with elongation factor 1-α 2 (eEF1A2), known to be overexpressed in breast cancer and MM cells, targeting the noncanonical role of the protein and leading to a proapoptotic response. Following the drug's approval from Australian regulatory authorities, eligible patients will have access to a new first-in-class drug to treat MM, expanding the current anti-MM portfolio. Plitidepsin (Aplidin; PharmaMar) was approved in combination with the corticosteroid agent dexamethasone, to treat MM patients who failed or became resistant to other therapies, covering the third- and fourth-line treatment setting.<br />
DOI: 10.1358/dot.2020.56.5.3135886 PMID: 32406881 [Indexed for MEDLINE]<br />
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[5]. Curr Opin Investig Drugs. 2009 Jun;10(6):536-42.<br />
The mechanism of action of plitidepsin.<br />
Muñoz-Alonso MJ(1), González-Santiago L, Martínez T, Losada A, Galmarini CM, Muñoz A.<br />
Author information: (1)Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier, 4, E-28029 Madrid, Spain.<br />
Plitidepsin (PharmaMar SA) is a cyclodepsipeptide originally isolated from the Mediterranean tunicate Aplidium albicans, and has demonstrated strong anticancer activity against a large variety of cultured human cancer cells and in xenografted mice. Phase I/II clinical trials of plitidepsin yielded promising results of anticancer activity in patients with cancer. Several studies have revealed that plitidepsin induces cell cycle arrest or apoptosis in a cell type- and dose-dependent manner. These effects are related to the induction of early oxidative stress, the activation of Rac1 GTPase and the inhibition of protein phosphatases, which in conjunction cause the sustained activation of JNK and p38 MAPK. This review outlines the current knowledge of plitidepsin activity, with a primary focus on the molecular mechanisms of action of the compound.<br />
PMID: 19513942 [Indexed for MEDLINE]
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